C2006/F2402 '09 -- Outline for Lecture 23
(c) 2009 Deborah Mowshowitz . Last updated 04/27/2009 09:37 AM.
Handouts: (Not on web.) 23A -- kidney structure; 23B = Regulation of Blood Pressure; 23C = Cells involved in immune system; clonal selection
For a good set of notes on kidney function see the filtration & absorption page from David Currie. (http://faculty.etsu.edu/currie/filtreab.htm) Unfortunately, the pictures don't show up. I'm hoping we can restore them; if not I will try to find others.
Here's an article from the LA Times on the latest artificial kidney.
I. Kidney Structure
A. Overall structure -- see handout 23A or Sadava fig. 51.9
1. Kidney has medulla (inner part) and cortex (outer)
2. Functional unit = nephron (Sadava 51.7 )
3. Visible unit (in medulla) = Renal Pyramid = bottoms of many nephrons
4. Tops of nephrons in cortex
B. Structure of Nephron -- see handout 23A or Sadava fig. 51.7 & 51.9 . For EM pictures see Sadava 51.8. (We may do the parts as we need them, but all are summarized here.)
1. Nephron itself -- parts in cortex
a. Bowman's capsule
b. proximal (convoluted) tubule
c. distal (convoluted) tubule
2. In medulla
a. Loop of Henle
b. Collecting duct (shared by many nephrons)
3. Capillaries (discussed last time)
a. 2 sets in series
(a). form glomerulus inside Bowman's capsule
(b). function in filtration
(a). surround tubules
(b). fyi: part in medulla (surrounding loop of Henle) is called the vasa recta
(c). function in secretion & reabsorption
b. How capillaries connected. Circulation goes as follows:
Artery (from heart) → afferent arteriole → glomerular capillaries → efferent arteriole → peritubular capillaries → venule → vein (back to heart)
II. Kidney Function
A. Function of Nephron -- Let's follow some liquid through.
1. Filtration in glomerulus
2. Reabsorption (of most substances) occurs in proximal tubule
a. Many substances removed from lumen by secondary act. transport
(1). examples: glucose and amino acids
(2). Cross apical/luminal surface of epithelial cell by Na+ cotransport
(3). Exit basolateral side of cells into intersit. fluid by facilitated diffusion
(4). Process is similar to absorption in cells lining intestine
b. Na+/K+ pump on basolateral side keeps internal Na+ low.
c. Water follows salt.
3. Loop of Henley -- overall picture of state of filtrate
a. Definition: Osmolarity (Osm) = total solute concentration = concentration of dissolved particles = osmol/liter. (One osmol = 1 mole of solute particles.)
Examples: 1M solution of glucose = 1 Osm; 1M solution of NaCl = 2 Osm.
b. Events in Loop
(1). Descending: Osmolarity increases as filtrate descends due to loss of water
(2). Ascending: Osmolarity decreases as filtrate ascends due to loss of salt; reaches min. value less than that of blood. Therefore can excrete urine that is hypo-osmotic (less concentrated) than blood.
(3). Overall: Net effect of going through countercurrent loop -- less volume, less total salt to excrete (even if filtrate and blood are iso-osmotic when done).
4. Distal Tubule & Collecting Ducts
a. Removal (reabsorption) of remaining Na+ -- Events in distal convoluted tubule (& first part of coll. ducts) depend on aldosterone -- aldost. promotes reabsorption of Na+ (and secretion of K+). See handout 22C, top right.
b. Volume Control -- occurs in collecting ducts. Events in collecting duct (volume control) depend on ADH -- Osmolarity will increase (and volume decrease) in collecting duct if ADH (vasopressin) present and water removed. (Details below.)
B. Details of Transport Events in Loop of Henley (See Sadava 51.10)
1. Water permeability. Luminal cell membranes in descending loop and lower part of ascending loop are permeable to water.
2. Generating the Na+ gradient in the medulla.
a. Luminal cell membranes in rest of ascending are impermeable to water and pump NaCl from lumen to interstitial fluid.
b. NaCl pumped out from ascending loop accumulates in medulla, forming a gradient of increasing osmolarity (outside the tubule) as reach bottom of loop = core of medulla.
3. Water loss: Filtrate from proximal tubule loses water as it descends into medulla → NaCl stays in tubule → high concentration NaCl in tubule→ to be removed in ascending. (Na+ not pumped out of these cells on BL side.)
4. Escalator Effect: If NaCl diffuses into descending loop, it is carried around and pumped out in ascending = escalator effect.
5. Why called countercurrent? Because flow in two sides of loop is in opposite directions physically and with respect to osmolarity. First leg (descending) of loop removes water → higher osmolarity in filtrate; second leg (ascending) removes salt → lower osmolarity in filtrate.
See problems 12-1 to 12-3.
C. Distal Tubule and Collecting Ducts -- Details
a. Filtrate entering distal tubule is at minimum osmolarity
b. Hormones cause water and/or Na+ to be removed (reabsorbed from filtrate)
aldosterone affects Na+ reabsorption (& K+ secretion)
ADH affects water reabsorption
2. Role/Mech. of action of ADH
a. ADH (using cAMP) stimulates insertion of water channels/pores into membranes of collecting duct (and maybe late distal tubule)
b. Water flows out ADH-stimulated channels (if in membrane) because of salt gradient in medulla.
c. Diabetes insipidus -- result of no ADH or no response to ADH
3. Role of aldosterone (in water/Na+ balance)
a. Promotes reabsorption of Na+; water follows (not necessarily in same part of tubule).
b. Amount of Na+ reabsorbed due to aldosterone is small % of total, but adds up; affects blood pressure.
4. Question to think about: Where are the receptors for ADH? Aldosterone?
See problems 12-8 to 12-13 & 12-15.
II. Regulation of kidney function See Sadava sect. 51.6.
A. Regulation of release of ADH from post. pituitary (See Sadava fig. 51.14)
1. Sensors -- 2 types, since regulating two different variables
a. Stretch receptors in arteries (sensors for blood volume) -- this comes into play only if large volume change
b. Osmo-receptors in HT (sensors for solute levels in blood) -- this is the primary sensor
2. Response: ADH release up if osmolarity of blood up or stretch receptors (way) down
3. Thirst: ADH release & thirst both triggered by same receptors.
4. Feedback Loop: ADH release (& thirst up) → water intake up, water loss down in kidney, & constriction of arterioles in extremities* → restore blood volume, reduce osmolarity (and restore blood pressure)
*Remember ADH = vasopressin
5. Speed: Effects of ADH are relatively fast -- no prot. synthesis required. (Effect on water loss takes a while, since ADH affects formation of new urine, not state of pre-existing urine.)
B. Regulation of GFR & release of aldosterone
1. What is GFR? GFR = glomerular filtration rate = measurement of flow through kidney. GFR must be adequate to keep kidneys functioning properly. Flow is adjusted through local effects and overall control of blood pressure.
2. Autoregulation -- Local GFR Adjustments -- dilate/constrict afferent arteriole
Low BP (low flow through kidney) → dilation of afferent arteriole (to glomerulus) → increases flow through kidney → increase in GFR. High BP has opposite effect.
See problem 12-4.
3. Renin/Angiotensin/Aldosterone System
a. Low BP or GFR in Kidney → kidney secretes renin
b. Renin catalyzes rate limiting step in conversion of angiotensin precursor (in blood) → angiotensin II (active)
c. Major Effects of Angiotensin II
(1). Acts on adrenal cortex → aldosterone → Na+ reabsorbed in kidney and elsewhere
(2). Acts directly to raise BP -- is vasoconstrictor.
(3). Note that effects of aldosterone are slower than others as they involve steroid → binding to receptor → synthesis of new protein
See problems 12-7, 12-14, and 12R-4. By now you should be able to do all of problem set 12. (For 12-6 & 12-16, consider the max. osmolarity of urine. It's 1200 mOsm -- less than sea water.)
III. Summary of regulation of blood pressure (see handout 23B. & Sadava Sect. 49.5 --figs. 49.17 & 49.18 (49.18 & 49.19) )
A. Co-ordination of control
1. Major circuit that controls BP
a. IC = cardiovascular control center in medulla -- part of brain stem (Sadava fig. 49.18 [49.19]).
b. sensors = stretch receptors (= baroreceptors) in major arteries
c. effectors = heart, peripheral blood vessels (constrict/relax)
d. circuits -- uses PS and S.
See problems 11-10 & 11-16.
2. IC has other inputs and outputs
a. Additional input from
(1). chemoreceptors in arteries (for oxygen)
(2). chemo- and baro- receptors in higher brain
b. Additional output -- to adrenal medulla through sympathetic system (→ epinephrine)
3. Other effectors/sensors operate independently of IC (Sadava 49.17 [49.18])
a. HT controls production of ADH/vasopressin & thirst -- system effects vasoconstriction, water intake & conservation.
b. Renin/angiotensin/aldosterone system controlled by kidney GFR (& other inputs) -- systemic effects on vasoconstriction and salt (therefore water) retention
c. These factors affect both blood volume and capacitance of blood vessels
For Review Problems on Physiology, see Problem Set 12R.
IV. Specific (= Adaptive) Immune Response -- Major cells and Features
We have already discussed antibodies as chemical reagents. How do antibodies, and the entire immune system, really work physiologically? (Sadava, Chap. 18)
A. Specific Immune system has 2 branches
1. In both branches: Cells make a specific protein that binds to a foreign substance = antigen. Protein and antigen match up like ligand and receptor (or enzyme and substrate). Binding of specific protein to its target antigen is specific, and usually leads to destruction of target.
2. Humoral response -- Specific cell protein is an antibody. Why 'humoral?' Binding and destruction of antigen done by proteins in "humors" = antibodies in blood and secretions (for ex. milk, tears).
Example: B cells → release antibody → Ab (antibody) binds Ag (antigen -- usually on surface of microbe) → trigger destruction of microbes (microbes are engulfed by phagocytes or lysed) often with the help of a set of proteins called complement. (See Sadava 18.10 (18.11) & table below.) Allergies are a side effect of this system.
3. Cellular or cell-mediated response -- Specific cell protein is on surface of T cells, not released. Protein is called a TCR (T cell receptor). Binding and destruction of antigen done by whole cells bearing a TCR.
Example: T cells → TCR on surface; TCR's (of cytotoxic T cells) bind to Ag on surface of virus infected eukaryotic cell → destroy target cell by triggering apoptosis (programmed cell death). This is probably why grafts fail; foreign cells of graft look like infected (defective?) cells and are destroyed.
4. Big difference between the two branches -- Location of Target (as well as specific protein)
a. Humoral Response. Antibody (B cell protein) binds to antigens in solution or on surfaces of bacteria & viruses. Neither the protein mediating the immune response (antibody) nor its normal target (antigen) are on eukaryotic cell surfaces.
b. Cell-Mediated Response. TCR binds only to antigens on surfaces of other eukaryotic cells. Both the protein mediating the immune response (TCR) and its target must be on eukaryotic cell surfaces.
B. What Cells are involved? What are B cells and T cells? See handout 23C. White blood cells (leukocytes) -- contain no hemoglobin. WBC divided into two main types
1. Phagocytes -- macrophages, dendritic cells, etc. ( See Sadava fig. 18.2). Involved in processing antigens so lymphocytes can respond to them, and/or engulfing (& destroying) antigens identified by the immune system.
2. Lymphocytes. Found in lymph nodes and elsewhere. Do actual production of antibodies and/or execution of cellular immune response.
a. Divided into B and T cells.
(1). Both B & T cells come from same line of stem cells in bone marrow.
(2). B cells mature in bone marrow; T cells in thymus
b. Role of B cells -- produce & secrete antibodies. Major players in humoral response.
c. Role of T cells -- Needed for cell-mediated responses (details next time). Two types
(1). Helper T's (TH) -- Required for function of both TC's and B's .
(2). Cytotoxic T's (CTL or TC ) -- Kill target cells.
D. What are the Important Features of the Adaptive Immune Response that need to be explained?
1. Specificity & Diversity -- each Ab or TCR is directed against one epitope or antigenic determinant (= piece of antigen -- see Sadava sect. 18.3 (fig. 18.6), and there are many, many different antigens. How can you make so many different Ab's or TCR's, each specific for a particular antigen or piece of it?
2. Memory -- secondary response is faster, larger, better than primary response. In secondary response, make more Ab, Ab is more effective (binds better to Ag because of slight changes in amino acid sequence of Ab), and Ab response lasts longer. (Sadava 18.8; 7th ed only) How is this done?
3. Tolerance -- can distinguish self/nonself or normal/abnormal -- make Ab only to foreign/abnormal stuff (except in disease states). TCR only directed against infected cells, not normal ones. How does this work?
4. Response is adaptable -- response depends on amount and type of antigen (& history of previous exposure). How do you "know" which antibody (or TCR) to make in response to a particular antigen?
5. How do helper T cells fit in? How do helper T's and cytotoxic T's distinguish their targets?
V. Clonal Selection -- How do you account for the "important features" listed above?
A. B cells (See Handout 23C bottom = Sadava fig. 18.6 (18.7))
1. Each cell differentiates → produces a single type of Ab on surface (Cell called a "virgin" or "naive" B). Each cell makes a unique antibody -- that is, with a unique set of "grabbers."
2. Ab on surface of cell acts as a "trap". Surface antibody acts as trap/receptor for Ag. (Surface antibody also called BCR or B cell antigen receptor in parallel to terminology for TCR.)
3. Activation or destruction of B cell is triggered by binding of Ag to surface Ab (BCR)
a. Destruction. If Ag is perceived as "self" → cell destroyed or suppressed (→ tolerance).
b. Activation. If Ag is perceived as foreign → cell divides → clonal expansion, further differentiation into
(1). Effector cells -- short lived but secrete lots of Ab → destroy or inactivate targets; class of Ab determines fine points. (In earlier lecture we explained how alternative splicing can allow cell to switch from making surface bound Ab to secreted Ab.)
(2). Memory cells -- long lived and more specialized to make Ab; wait for next time (responsible for memory).
c. Whether antigen is perceived as "self" or "foreign" depends on time of exposure to the antigen (embryonic vs adult) and additional factors. (This turns out to be very complicated, so we will ignore the "additional factors.")
4. What's the point?
a. Clonal Selection: Each cell makes a little Ab before any Ag present. Each cell makes a different Ab. This antibody stays on the cell surface and acts as BCR = trap for antigen. Ag acts as a trigger -- binding of Ag to "trap" stimulates only those cells that happen to make Ab that binds to that particular trigger.
b. Clonal expansion: The cells triggered by binding of Ag grow and divide → (more) effector cells & memory cells . Both types of cells make only the antibody that binds to the trigger Ag.
c. Clonal suppression: The cells triggered by binding of self Ag are destroyed or suppressed (prevented from multiplying &/or making Ab.)
d. What does this explain?
1. Clonal selection is the part that accounts for specificity, diversity, and adaptability. How you make the 'right' antibody at the right time.
2. Clonal expansion and suppression are the parts that account for memory & tolerance -- memory when Ag triggers expansion (as in b) , and tolerance when Ag triggers destruction or suppression (as in c) .
5. Why do you need helper T cells? For most antigens, helper T must bind to B cell-Ag complex in order to activate B cell. (Activated cell makes secreted Ab.)
B. T cells -- similar process as with B cells -- one type of protein (TCR not BCR) with unique binding site made per cell -- but there are differences. More details next time.
C. Clonal vs. Natural Selection. Note how clonal selection and natural selection compare. In both cases, need to have many variants (diff. antibodies or dif. organisms) to be able to respond to unpredictable environmental challenges. How is this done? In both cases, make many variants and conditions select (promote propagation of) cells making the few suitable Ab (or carrying out a rare, useful function); the rest are wasted. Random generation of variants seems wasteful, but is the biological solution to preparing for change without conscious planning ahead.
Next time (last official lecture!! Lecture 25 is optional.): Wrap up of whatever we don't cover above, plus how helper T cells work, role of MHC, Ab structure and Ab genes. Leave problem set 13 until after lecture 24.